Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-5641 Wissenschaftlicher Artikel Kleinschnitz, Christoph; Grund, Henrike; Wingler, Kirstin; Armitage, Melanie E.; Jones, Emma; Mittal, Manish; Barit, David; Schwarz, Tobias; Geis, Christian; Kraft, Peter; Barthel, Konstanze; Schuhmann, Michael K.; Herrmann, Alexander M.; Meuth, Sven G.; Stoll, Guido; Meurer, Sabine; Schrewe, Anja; Becker, Lore; Gailus-Durner, Valerie; Fuchs, Helmut; Klopstock, Thomas; de Angelis, Martin Hrabe; Jandeleit-Dahm, Karin; Shah, Ajay M.; Weissmann, Norbert; Schmidt, Harald H. H. W. Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy. 2010 urn:nbn:de:bvb:20-opus-68416 Neurologische Klinik und Poliklinik OPUS4-12419 Wissenschaftlicher Artikel Radermacher, Kim A.; Wingler, Kirstin; Kleikers, Pamela; Altenhöfer, Sebastian; Hermans, Johannes J. R.; Kleinschnitz, Christoph; Schmidt, Harald H. H. W. The 1027th target candidate in stroke: Will NADPH oxidase hold up? As recently reviewed, 1026 neuroprotective drug candidates in stroke research have all failed on their road towards validation and clinical translation, reasons being quality issues in preclinical research and publication bias. Quality control guidelines for preclinical stroke studies have now been established. However, sufficient understanding of the underlying mechanisms of neuronal death after stroke that could be possibly translated into new therapies is lacking. One exception is the hypothesis that cellular death is mediated by oxidative stress. Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources. Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS. Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4. Here we discuss the state-of-the-art of this target with respect to stroke and open questions that need to be addressed on the path towards clinical translation. 2012 Experimental and Translational Stroke Medicine 4 11 urn:nbn:de:bvb:20-opus-124197 10.1186/2040-7378-4-11 Neurochirurgische Klinik und Poliklinik